Medicament Delivery Device and a Method of Medicament Delivery

ABSTRACT

A medicament delivery device and method of delivering a medicament is provided wherein the device is insertable into the uterine myometrium for the delivery of medicaments to the pelvic area and organs thereof, for example, the bladder, peritoneum, the vulva, vagina, fallopian tubes, ovaries, and uterus, and then to the bloodstream.

This application is a continuation of U.S. patent application Ser. No.10/550,699, filed Sep. 27, 2005, which is the U.S. national stageapplication of International Patent Application No. PCT/GB04/001390,filed Mar. 26, 2004, which claims priority to and the benefit of UnitedKingdom Patent Application No. 0307082.8, filed Mar. 27, 2003, thecontents of each of which are incorporated by reference herein.

This invention relates to a medicament delivery device and a method ofdelivering a medicament. In particular, but not exclusively the presentinvention relates to a device and a method for a providing an implant inthe uterine myometrium (in females) or prostate gland (in males) and thedelivery of medicament to the pelvic area and organs thereof, forexample the bladder, peritoneum, and in females the vulva, vagina,fallopian tubes, ovaries and uterus and then into the bloodstream.

There are many drugs which may be administered to the human and animalbody for the prevention or treatment of disease. Different types ofdrugs call for different ways of administering the drug to the human oranimal body.

Currently, most benign gynecological conditions, for exampleendometriosis or fibroids, are treated using traditional methods ofmedicament or drug delivery, primarily oral and intravenousadministration. Where possible, drugs are provided in pill, capsule,powder or liquid form for oral administration to a human or animal. Thedrug is then absorbed by the digestive system and will usually enter theblood stream via the liver to take effect. However, far from all drugsare suitable for such administration. For example, many drugs are brokendown by the digestion process and destroyed before they can enter theblood stream. This problem is caused by what is commonly referred to asthe “first pass liver metabolism” of the human or animal body, i.e. theprocess by which all substances absorbed by the digestive system mustpass through the liver into the blood stream. Therefore, to providesufficient drug to the female reproductive organs, relatively largedoses of a drug are required. These large doses can cause side effects.

To avoid or minimise the problem of the first pass liver metabolism,drugs can be provided by injection, for example drugs desired to take aninstant effect in the blood stream of a human or animal body may beinjected into a vein, i.e. intravenously. Alternatively, drugs may beinjected into muscle tissue from which the drug is absorbed more slowlyinto the blood stream. Drugs for injection into muscle tissue may, forexample, be provided in an oily base which helps to regulate the rate ofabsorption. However, injections can be painful and difficult,particularly injections into muscle tissue, and can lead to tissuedamage where frequent injections are required on a long term basis, e.g.of insulin for diabetics.

Other types of drug delivery include nasal sprays for administration ofdrugs to the nasal tissues and lungs; patches, such as the Nicorette®patch, for the application of Nicotine, or Ortho Evra, a contraceptivepatch which releases estrogen/progesterone through the skin; and lotionsor ointments for topical application, i.e. directly to an affected partof the body.

However, these alternative types of drug delivery means can suffer fromdisadvantages. For example, skin patches can cause skin irritation,suffer from disattachment and cause cosmetic issues.

Although the above drug delivery methods are useful for particular typesof drugs and medicines, with the exception of intramuscular depotinjections, they are unable to provide therapeutic levels of drugs overa long term, e.g. weeks, months and years rather than days, withoutrepeated application by the patient, a career, physician or generalpractitioner.

For application of drugs on a long term basis, various implants havebeen developed. One such type of implant may be inserted under the skinand have a mechanism for slowly releasing a drug into the blood streamof the human or animal in which it is implanted. For example, Norplant®or Implanon® comprise an implant having small capsules or rods whichslowly release levonorgestrel or etonorgestrel into the blood stream toprovide a contraceptive effect for women. Norplant® can be effective forup to five years.

However, these implants inserted under the skin suffer from a number ofdisadvantages. In particular the insertion of such an implant ispainful, can cause significant bruising and discomfort at the implantsite and requires local anaesthesia on both insertion and removal. Inaddition, as such implants are placed under the skin in for example thearm, they can be visible and cause discolouration of the skin.Furthermore, as the arm contains many different types of tissue andplanes of tissue, movement of the implant along or through these tissueplanes can occur. This can mean the implant moves to locations otherthan where it was placed during insertion which can lead tocomplications for the patient, in particular during removal of theimplant. Difficulties with the Norplant® implant has led to it beingwithdrawn from clinical use.

For gynecological conditions, long term local drug delivery through thevagina or endometrium is useful to deliver drugs to the pelvic regionand organs thereof for example to the bladder, peritoneum, vulva,vagina, ovaries and uterus.

Current delivery means include vaginal creams, gels, intrauterinedevices (contraceptive coils, IUD or IUCD) and vaginal rings or tampons.

Intrauterine devices (IUDs) are placed in the endometrial cavitytypically to provide a contraceptive effect. For example, Leiras(Schering AG) market an intrauterine device called Mirena which releases20 mcg of levonorgestrel, to reduce the thickening of the endometrium ofthe uterus, each day for up to 5 years.

Vaginal rings, comprising soft plastic rings of around 4 cm to 5 cm indiameter impregnated with a is desired drug, are placed in the vaginaaround the cervix where they slowly release a drug into the bloodstreamthrough the soft tissue of the cervix. Organon's Nuvaring releasesoestrogen/progesterone.

Although the above provide long term local drug delivery to the pelvicregion, for various reasons, they tend to suffer from low levels ofpatient compliance.

Typically creams and gels are considered by patients to be messy andunhygienic while vaginal rings can be uncomfortable, particularly duringsexual intercourse, and may cause discharge. Intrauterine devicesrequire inconvenient regular visits to the clinic for physician fittingand can cause severe discomfort such as stomach cramps due to the directapplication of levonorgestrel to the endometrium of the uterus. Inaddition, such intrauterine devices may cause discharge, menstrualdisturbance and fertility effects.

It is an aim of the present invention to provide means to delivermedicaments to the pelvic region which minimises the above difficulties.

According to the present invention there is provided an implantablemedicament delivery device which is insertable into the myometrium orprostate comprising means capable of providing controlled delivery of amedicament over a period of time.

A medicament may be any pharmaceutical, neutraceutical, prophylactic ortherapeutic agent wherein a therapeutic agent includes, but is notlimited to, means for radiotherapy such as radioactive sources forexample caesium, iridium, radioactive iodine, radioactive strontium orradioactive phosphorus.

The term “medicament” herein also includes energy sources which may bedelivered to the myometrium by targeting the delivery device. Suchenergy sources include electromagnetic radiation, heating and coolingenergies such as to selectively destroy tissues.

Preferably the medicament delivery device is an implant which can beinsertable into the myometrium, or prostate and retainable therein for adefined period of time.

The retention of the implantable delivery device in the myometrium (infemales) or prostate (in males) provides for direct and local deliveryof a medicament to the pelvic region and organs thereof for example thebladder, peritoneum, bloodstream and in females the vulva, vagina,ovaries, fallopian tubes and uterus over a determined period of time.

Preferably the implantable delivery device is capable of beinginsertable in and retainable in the smooth muscle myometrial tissue ofthe cervix.

Insertion and retention of the implantable medicament delivery device inthe myometrium of the cervix enables the implant to be checked andmonitored by speculum examination or other visualisation or palpationfollowing implantation.

Alternatively the implantable delivery device may be inserted in anysuitable location in the myometrium, usually of the body of the uterus.The implant may be placed in the myometrium of the body of the uterus,or other positions not accessible by access via the vagina.

Preferably the implantable medicament delivery device comprises a bodyhaving an outer surface and opposing first and second ends said bodycomprising a medicament wherein the first end of the body is asemi-sharp point.

A semi-sharp point enables the tissue to be sufficiently disrupted toallow insertion of the implantable device, but causes minimal tissuedamage.

In one preferred arrangement the body of the device is elongate and thesecond end of the body includes a head portion wherein the head portionis a lateral extension from the longitudinal axis of the elongate body.

Preferably the head portion is a substantially flat plate which extendsin all radial directions from the second end of the body of the device.

The provision of a semi-sharp point at a first end of the deliverydevice is advantageous as it allows the device to be easily insertedinto the smooth muscle of the myometrium or the tissue of the prostate.

Preferably the means capable of providing the controlled delivery of amedicament over a period of time is a pharmaceutically acceptablecarrier such as at least one of a hydrogel, a silicone based material,elastomer, proteinaceous material, polyethylene glycol (PEG) material,polysaccharide or other carbohydrate material, microspheres, polymericmaterial or plastics material which may comprise, be contained by, orcoated onto the device, or other means known to those skilled in theart.

Preferably the means capable of providing the controlled delivery of amedicament are present in the body of the device.

Alternatively, in those embodiments wherein there is a head, the meanscapable of providing the controlled delivery of a medicament may bepresent in the head of the device.

In particular embodiments the means are present in both the body and thehead of the device.

In embodiments where the means capable of providing the controlleddelivery of a medicament are provided in the body of the device,medicament delivery is substantially through the myometrium to thetissues and organs of the pelvic region.

In embodiments where the means capable of providing the controlleddelivery of a medicament are provided in the head of the device,medicament delivery is substantially to the vaginal cavity and tissuesand organs of the pelvic region.

Preferably the second end of the device includes retrieval means.

Retrieval means are advantageous as they allow the implant to be removedfrom the myometrium or prostate tissue after a determined period oftime. Thus the delivery, device can be easily removed from the body anddoes not require to be retained in the body forever. Removal of theimplantable device provides a means of control over the length of timean active agent of a medicament is delivered.

The retrieval means can be any means which allow the removal of theimplantable device from the myometrium or the prostate following adetermined period of time.

In arrangements of the device which are insertable and retainable in themyometrium, preferably the retrieval means comprises an elongateflexible member, for example a thin length of cord, twine or fibre orstring.

Preferably the elongate flexible member can be left outside themyometrium and soft tissue surrounding the uterus and/or vaginal cavitywithout causing irritation to a patient, nor affecting sexualintercourse. When it is desired to remove the implantable deliverydevice from the tissues in which the implant is inserted, for examplethe myometrium, the flexible member can be manipulated to pull theimplant out of the tissue.

Preferably the second end of the device for example the head and/orretrieval means remain visible or palpable during examination by aphysician when, in use, the delivery device is inserted into themyometrium or prostate.

This is advantageous as the location of the implantable delivery devicecan be easily monitored and checked by visual or physical inspection.

Preferably, the overall implantable device of the present invention issignificantly smaller than the overall size of coils. IUD or vaginalrings. This is advantageous as there will be less discomfort to theperson in which the drug delivery device is implanted and lesslikelihood of rejection of the implant by the body or responses such asinflammation.

Preferably the device has an axial length in the range 5 mm to 45 mm.

More preferably the device has an axial length in the range 10 mm to 45mm.

Preferably the device has a diameter of from 0.5 mm to 4 mm.

Preferably the body has a large surface area to volume ratio. This hasthe advantage of providing maximal absorption of the drug into thesurrounding tissues and/or smooth muscle.

The device of the present invention may be used to deliver a wide rangeof active agents for example, but not limited to, steroids, hormonessuch as a progestin, agents which promote a contraceptive effect, forexample levonorgestrel or etonorgestrel, agents for treating disordersof the pelvis, for example, GnRH analogues, NSAIDs, COX-II inhibitorsand aromatase inhibitors, vagina and organs and tissues thereof,cytotoxic agents for killing cancer cells or treating cancer,particularly cancer cells of the bladder, prostate or cervix or otherpelvic malignancies and agents for the treatment of benign prostatichypertrophy, impotence, erectile dysfunction and the like. Further, thedevice may be used to deliver agents for the treatment of an over activebladder, such drugs including anti-cholinergic drugs or calciumantagonists, or agents for radiotherapy.

Preferably the medicament of the device is chosen from the groupconsisting of, but not limited to, anti-infectives, antimicrobials,antivirals, antibiotics, anti-allergenics, anti-inflammatories,anti-fungals, anti-cholinesterases, nutritional agents such as essentialamino-acids, fats and vitamins, prebiotics, probiotics and acidifiers,cardiovascular agents, anti-hypertensive agents and chemotherapeuticagents.

Preferably the medicament is a therapy for oestrogen dependentproliferative disorders of the pelvis, for example endometriosis and/orfibroids and other pelvic disorders as would be known to those skilledin the art for example functional cysts and polycystic ovary syndrome.

Preferably said therapy for endometriosis includes progestins, BnREagonists and antagonists, NSAIDs, COX-II inhibitors, combined oralcontraceptives, Danazol, smooth muscle relaxants or aromataseinhibitors. The skilled person would also appreciate other similartherapies which could be used in relation to such disorders and thesuitable dosage that would be required.

A drug delivered by the present invention may additionally oralternatively include a microbicide. A microbicide is any agentdetrimental to, or destructive of, the life of microbes, viruses orbacterial organisms. Such a microbicide could be used to destroyorganisms responsible for sexually transmitted diseases such asgonorrhoea, chlamydia, genital herpes, Human Immunodeficiency Virus,Human Papilloma Virus or bacterial vaginosis.

The concentration and the time period over which the above active agentsand those described below should be provided will be as determined bythose skilled in the art. Those skilled in the art can determine theseparameters, which depend on for example the potency (the amount requiredto effect the desired change), toxicity and in vivo diffusion of theactive agent using standard procedures.

Preferably, in use, the cumulative release of therapeutic agent is in anamount selected from 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 95%, 99% and 100% relative to the total amount of medicamentin the device after implantation for a period of 1 week, 2 weeks, 1month, 2 months, 3 months, 4 months, 6 months, 1 year, 2 years, 3 years,4 years or 5 years.

According to a second aspect of the present invention there is provideda kit for implanting a device of the first aspect of the inventioncomprising

-   -   a device according to the first aspect of the invention and an        insertion tool, said tool comprising an elongate shaft, said        shaft having handle means at a first end thereof and device        mounting means at a second opposite end wherein the medicament        delivery device of the first aspect of the invention is        mountable on the insertion tool.

According to a third aspect of the present invention there is provided amethod of providing a medicament to a female mammal comprising the stepof inserting a device according to a first aspect of the invention intothe myometrium.

The implantable delivery device is capable of being inserted into thesmooth muscle myometrial tissue of the cervix via the vagina, into themyometrium of the uterine body through serosa surrounding the myometriumduring open or laparoscopic surgery or into the myometrium through theendometrial cavity.

Preferably the method of the third aspect of the invention comprises thesteps of

-   -   a) providing the implantable medicament delivery device of the        first aspect of the invention,    -   b) introducing the medicament delivery device into the body via        the vagina,    -   c) penetrating the myometrium with the medicament delivery        device, and    -   d) inserting the medicament delivery device into the myometrium.

Preferably the method further comprises the step of mounting theimplantable medicament delivery device on an insertion tool.

Particular embodiments of the medicament delivery device are implantablein the prostate. The prostate is a gland in males which surrounds theurethra below the bladder.

Preferably the implant is insertable into the prostate by a transrectalroute. Alternatively the implant can be inserted into the prostate by atrans-perineal route.

Preferably the medicament delivery device is insertable into theprostate using ultrasound.

Provision of an implantable medicament delivery device in the prostatehas the advantage that drugs can be delivered to the tissue of theprostate, tissue surrounding the prostate, and the bloodstream. Further,delivery of drugs directly to the prostate means the drugs are notsubjected to liver metabolism as would be the case for drugs providedorally.

Preferably the prostate implantable medicament delivery device providesfor the cumulative release of a therapeutic agent in an amount selectedfrom 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%and 100% relative to the total amount of medicament in the device afterimplantation for a period of 1 week, 2 weeks, 1 month, 2 months, 3months, 4 months, 6 months, 1 year, 2 years, 3 years, 4 years or 5years.

According to a fourth aspect of the present invention there is providedthe use of a delivery device according to the first aspect of theinvention to provide long term local delivery, for example 3 months to 5years, of medicaments to the pelvic region and organs thereof, forexample to the bladder, peritoneum, vulva, vagina, ovaries and uterus.

In one preferred embodiment of the fourth aspect of the invention adevice according to the first aspect of the present invention is used todeliver medicament(s) to treat gynecological conditions, for exampleendometriosis, fibroids, cervical cancer or overactive bladder.

In a second preferred embodiment of the fourth aspect of the invention adevice according to the first aspect of the present invention is used totreat male conditions for example benign prostatic hypertrophy,impotence, erectile dysfunction and the like.

The medicament delivery de-vice and method of the present inventionpromote smooth, controlled release of drugs to the pelvic region, whichallows absorption of drugs without subjecting drugs to liver metabolism.

Embodiments of the present invention will now be described by way ofexample only with reference to the accompanying drawings, in which:

FIG. 1 is an illustration of an implantable medicament delivery deviceaccording to the invention for delivery of medicament to the tissues ofthe myometrium and pelvic region;

FIG. 2 is an illustration of an implantable medicament delivery deviceaccording to the invention for delivery of medicament to the tissues ofthe vaginal cavity and pelvic region;

FIGS. 3, 4, 5 and 6 are illustrations of embodiments of the medicamentdelivery device according to the invention;

FIG. 7 is a saggital illustration of the female pelvic region of amedicament delivery device of FIG. 1 in use;

FIG. 8 is an end view of the illustration in FIG. 4 along the line A-Aillustrating the placement of the device;

FIG. 9 is a coronal view of the illustration in FIG. 4 along line B-B;

FIG. 10 shows an illustration of the embodiment of a medicament deliverydevice as shown in FIG. 1 mounted on an insertion tool;

FIG. 11 shows an illustration of the embodiment of a medicament deliverydevice as shown in FIG. 2 mounted on an insertion tool;

FIG. 12 shows an illustration of an embodiment of device mounting meanswherein the mounting means are formed by a stepped protrusion on theinsertion tool capable of cooperating with a depression provided on thedelivery device;

FIG. 13 shows an embodiment of a handle means of an insertion tool; and

FIG. 14 is an illustration of an embodiment of an implant of the presentinvention inserted in the prostate.

Referring to FIG. 1, in one embodiment, the implantable medicamentdelivery device comprises an elongate cylindrical body 2 with a firstend 4 and a second end 6. In this embodiment head portion 8 extendslaterally from the second end 6 of the body such that a flange isprovided around the circumference of the body 2 at the second end. Asemi-sharp point 10 is provided at the first end 4 of the body 2. In theembodiment shown the head portion 8 is a substantially flat plate whichincludes a depression 12. When, in use, the body of the device isimplanted in the tissues of the myometrium, the head portion 8 minimisesthe likelihood of the tissue of the implant being pushed too far intothe tissue during insertion of the implant or the myometrium tissuegrowing over the implant. It also provides means by which the positionof the implant can be checked by visual or physical means.

In the embodiment described which is insertable into the myometrium,retrieval means 14 are provided by a cord. The cord extendssubstantially from the centre point of the depression 12 in the headportion 8. In use, the cord extends from the second end of the implantand allows the device to be removed from the tissue after suitabledelivery of the medicament or if the patient requests removal. Thedevice is typically retained in the body for at least a day, a fewweeks, months or up to 5 years. It may be removed at any point duringthis period. In embodiments wherein the device is comprised ofbiodegradable material the device may not need to be removed at a latertime point and thus will not require a head portion or retrieval means.

In this embodiment the means capable of providing controlled delivery ofthe medicament is located in or on the elongate body 2 of the device.Delivery of the medicament is substantially through the myometrium andinto pelvic organs and tissues. This embodiment of the device isparticularly advantageous for the delivery of medicament for thetreatment of endometriosis and or fibroids.

FIG. 2 shows an embodiment of the present in invention wherein theelongate body 2 may be shorter in length, approximately 5 mm to 20 mm inlength and in which the head portion 8 is larger typically around 12 mmin width. In such an embodiment the means capable of providingcontrolled delivery of a medicament over a period of time is located inor on the head portion.

In use, the body 2 is inserted in the tissues of the myometrium and thehead portion remains in the vaginal cavity. This embodiment of thedevice substantially delivers medicament to the vaginal cavity, mucosathereof and pelvic tissues, such an embodiment is particularlyadvantageous for delivery of medicaments suitable for treating bacterialvaginosis.

Alternative embodiments of the implantable device are illustrated byFIGS. 3 to 6. In these embodiments the body of the implant may be spiralor corkscrew shaped (FIG. 3), generally J or U shaped such that thesecond end of the implant forms a loop or hook (FIGS. 4 and 6) or anelongate mesh cylinder (FIG. 5). As shown in FIG. 4 a semi-sharp pointmay not be required at the first end of the body 4 to allow insertioninto the tissues.

The body may be any suitable shape which allows the implant to beinserted into the myometrium or prostate. Indeed the cross section ofthe body can be of any preferred shape, which allows insertion of theimplant into the myometrium or prostate, or that influences the drugdelivery characteristics of the implantable delivery device. For examplethe body of the device may be cross-shaped to increase the surface areaof the delivery device exposed to the surrounding tissue. Further, thebody may be formed by a mesh or other method to increase the surfacearea of the implant in contact with the myometrial or prostate tissue.The amount of surface area of the implant in contact with surroundingtissue or muscle can influence the drug delivery characteristics of theimplant.

As shown in FIGS. 4 and 6 the retrieval means may comprise a hook at thesecond end of the implantable device wherein the second end of the body2 is bent toward the first end to provide a hook. In this embodiment theretrieval means restricts the body 2 from becoming buried in the softtissue enabling retrieval of the implant from soft tissue and the smoothmuscle of the myometrium or the prostate, in addition, the hook providesmeans by which the location of the implant can be checked by a physicianby visual or physical means.

Alternatively, as shown in FIG. 3, the retrieval means can be a slotcapable of accepting a screwdriver or other means for rotating theimplantable delivery device in the tissue to insert or remove the devicefrom the tissue.

In the embodiment illustrated by FIG. 1 the body 2 comprises themedicament delivery means. In particular embodiments, not shown in FIG.1, a length of the body 2 between the point 4 and retrieval means 14 mayhave a reduced diameter relative to the diameter of the body 2 at thefirst and second ends 6. In such embodiments the drug delivery means maycomprise a cylinder of material formed around the reduced diameterportion of the body 2. The medicament delivery means can be any suitablepharmaceutically acceptable carrier for example, a hydrogel carrying theactive agent to be delivered by the medicament delivery device. Inanother example, the delivery means is a silicone based material,elastomer, proteinaceous material, polyethylene glycol (PEG) material,polysaccharide or carbohydrate material, microspheres, polymericmaterial or plastics material which may comprise, be contained by, orcoated onto the device. The above drug delivery devices may alsocomprise, be contained by, or coat the head 8 of the device. Thisallows, as discussed in relation to the embodiment illustrated in FIG.2, for delivery of medicament to the vaginal cavity.

In a preferred embodiment, the body of the implant which may be porous,non-porous or microporous, can be dipped into a solution of the selecteddrug delivery medium containing a solution or slurry of drug, such thata thin layer of drug and drug delivery medium is coated onto the body ofthe implant and bonds securely in the dry state to the body of theimplant via a mechanical or adhesive hold.

Alternatively, the medicament can be impregnated, or absorbed by or intothe device and allow the medicament to be released over time. As afurther alternative the medicament may be applied to the device usingany suitable means that allow the medicament to be attached or bonded tothe device and which allow the medicament to be available forabsorption/release into the surrounding tissues, for example themyometrium or vaginal cavity.

The drug delivery medium may be capable of slowly releasing the activeagent of the medicament into the myometrium, vaginal cavity or theprostate, and thus providing drugs to the pelvic region and organsthereof the surrounding soft tissues and blood vessels.

Hydrogel releases drug by diffusion or via microcracks in the hydrogel.An alternative biodegradable hydrogel system releases drug via anerosion or degradation mechanism. Varying release rates of drugs can beachieved, as can continuous dosing with small levels of drugs, andflexibility of drug release may depend on different drugs being utilised

Depending of the release characteristics of the hydrogel and thechemical composition of the active agent; release of the active agentwill typically occur up to 5 years from implantation of the deliverydevice.

The medicament delivery device may be formed by any biocompatiblematerial, for example the medicament delivery device can be formed fromplastics or biocompatible metals. Suitable materials include, but arenot limited to, high density polyethylene (HDPE), ultra high molecularweight polyethylene (UHMWPE), polypropylene (PP), polyvinyl chloride(PVC), polymethylmethacrylate (PMMA), polyethyleneterephthalate (PET),polytetrafluoroethylene (PTFE), polycarbonate (PC),styrene-butadine-styrene (SBS), stainless steel (361/316L/317), nickelfree stainless steel, cobalt chrome alloy (CoCrMo), titanium(specifically Ti6Al4V) and Liquid Metal.

In one particular embodiment of the delivery device, the delivery deviceis formed from the medium carrying the drug. In this example, if themedium carrying the drug is absorbable, the complete delivery device maybe absorbed by the body over the period of time that the drug isadministered.

Wherein the implant itself is the medium by which the drug to beadministered is carried it can be envisaged that an insertion device forexample a trocar containing the implant may be used to deliver theimplant. In this embodiment the delivery device may be pushed out of orinjected from the trocar into the myometrium 44. The use of an implantcomprising the medium in which the drug to be administrated is included,would allow insertion of the implant into the myometrium 44 and deliveryof the drug to be limited to a shorter time scale for example 1 day, 3months to 12 months. The implant would not require to be removed at alater date as it may degrade over time and be absorbed by the body.

The drug may be delivered to the myometrium 44 and be absorbed within afew minutes, hours, days or weeks depending on the medium. It can beappreciated that where the implant comprises the drug delivery medium,removal of the implant is not required. An absorbable implant thereforedoes not require retrieval means.

The uterine myometrium has few or no somatic pain fibres and thusinsertion, provision and withdrawal of the implant in the myometriumwill cause minimal pain and discomfort to the patient.

A device of the present invention capable of being implanted into themyometrium tissue is advantageous over subcutaneous delivery devicespreviously known in the art, such as Norplant® which are inserted underthe skin which has somatic sensory (pain) nerves.

As there is little tissue or muscle: movement in the myometrium comparedwith for example the tissues of the arm or the leg and the myometriumdoes not comprise as many layers or planes of tissue as in the arm orleg, there is little likelihood of the implant moving to a differentlocation following insertion.

As shown in FIG. 7, the female human genital area comprises a bladder30, urethra 32, vaginal cavity 34, cervix 36, uterus 38 and anus 40. Inparticular, the cervix 36, at a position between the vaginal cavity 34and uterus 38, comprises the cervical canal 42 leading from the vaginalcavity 34 into the uterus 38 and surrounding smooth muscle known as themyometrium 44. The myometrium is defined by the serosa 46 (an epitheliallayer of cells) and the endometrium 48. An end view of the cervix alongline A-A is shown in FIG. 8.

In use, an embodiment of the implant can be inserted into the myometriumvia the vagina and then through the cervix or alternatively may beinserted into the myometrium during open or laparoscopic surgery.

The myometrium of the cervix is in a convenient location, at the top ofthe vaginal cavity, for insertion and removal of the implant via vaginalaccess. Further insertion of the device by this route has the advantagethat the implant can be suitably located using a speculum in anoutpatient setting. The insertion of the implant in the myometrium wouldbe similar in both the time taken and the discomfort to the patient asthe taking of a smear.

Insertion of the implantable medicament delivery device during open orlaparoscopic surgery has the advantage of allowing the implant to beplaced at any suitable location in the myometrium, usually in the bodyof the uterus. The implant may thus be placed in the myometrium of thebody of the uterus, or other positions which would not be accessible byaccess via the vagina.

Location of the implant within the smooth muscle myometrial tissue ofthe cervix and uterus provides a novel means of drug delivery to thepelvic region and organs thereof for example to the bladder, peritoneum,vulva, vagina, ovaries and uterus. Local delivery of active agents of amedicament via insertion of the implant in the uterine myometriumpromotes rapid, efficient absorption of the active agent directly intothese organs the surrounding tissue and then the bloodstream. Further,delivery of medicaments in this way avoids the first pass liver effect.

The active insertion of the implantable delivery device into the smoothmuscle of the cervix of the uterine body means that the presentinvention differs from an IUD or a vaginal ring as an IUD is located inthe cavity of the uterus (endometrium) and vaginal rings are placed atthe top of the vagina around the cervix.

While inserted in the myometrium the device will not be felt by thepatient. As previously discussed, this provides a further advantage ofthe present invention over intrauterine devices and vaginal rings.Furthermore, the device of the present invention will not causemenstrual or fertility disturbances and will be acceptable to women of arange of religious faiths.

Moreover, drug delivery by means placed around tissues or in cavitiessuch as vaginal rings and intrauterine devices can suffer from decreasedabsorption as the active agents have to pass through epithelial layersoverlying the surrounding tissues before they enter the tissue. Forexample, drugs released from a vaginal ring must pass through thevaginal epithelium before being absorbed into the vaginal wall andpassing into the blood stream.

Locating medicament delivery means and delivery of the medicament in themyometrium minimises the risk of poor absorption as the active agentsare not required to pass through epithelium. Medicament absorption isfacilitated by high local blood flow.

In particular embodiments locating medicament delivery means in themyometrium and delivery of the medicament into the vaginal cavityenables delivery to the epithelium lining the vagina and the localtissues thereof.

Therefore drug delivery directly into the myometrium or vagina willlikely require smaller amounts of a drug to achieve significant clinicalaffect, substantially reducing the risk of side effects.

In specific embodiments of the medicament delivery devices, suitable fordelivery of drugs to the tissues of the myometrium, for example FIG. 1,the body 2 of the medicament delivery device typically has a diameter of2 mm and a length of 20 mm. These diameters and lengths are, of courserfor guidance only and other suitable dimensions will be apparent tothose skilled in the art. For example depending of the amount of drug tobe delivered the length of the body may be 20 mm or 30 mm.

FIG. 2 shows an embodiment of the device for delivery of drugs to thevaginal cavity. In this embodiment, the body is preferably around 5 to10 mm in length and the head is around 8 to 15 mm in width.

The implant may have any structure suitable for insertion and retentionin the smooth muscle of the myometrium or the tissue of the prostate.For example the implant may comprise barbed portions or surface patternsto promote retention of the implant in the myometrium or prostate. Thismay be advantageous if movement of the tissue in which the implant isinserted is likely to cause the implant to work loose and move from itsintended position.

To aid insertion of the medicament delivery device into the myometriumby a vaginal route an insertion tool may be used.

An embodiment of an insertion tool is shown in FIGS. 10 and 11 with theimplantable devices illustrated by FIGS. 1 and 2 respectively mountedthereon. In the embodiment shown, the insertion tool comprises a curvedstainless steel shaft 60 of approximately 20 to 25 cm in length andaround 2 mm in diameter. A handle element 62 of around 2 to 4 cm may beprovided on the shaft. A particular embodiment of a handle element isillustrated in FIG. 13.

A first end of the shaft is provided with device mounting means 74 and asecond end is provided with handle means 62. In the example shown thedevice mounting means, illustrated more clearly in FIG. 12, comprises astepped protrusion 66 which provides a surface 68 against which thesecond end of the implantable device can abut. In particular, as shownin FIG. 12 a protruding portion 70 of the device mounting means isreceived by the depression provided on the head portion 8 of theimplantable device. The cord 14 of the implantable device is pulledalong the length of the shaft 60 and is releasably fixable in a notch 72provided in the handle means 62 of the insertion tool. The fixing of thecord 14 in the notch 72 aids the mounting of the device on the shaft ofthe insertion tool.

The device is mounted on the first end of the insertion tool and thenthe device is introduced into the body via the vagina. Using theinsertion tool the device is advanced into the vagina 34 towards thecervix 36 and inserted into the myometrium 44. The point 4 of theimplant facilitates the easy insertion into the smooth muscle of themyometrium 44.

The device is inserted into the myometrium until only the head portionof the device or retrieval means remain outside.

After a determined period of time, the implant can be removed from themyometrium. Removal may be due to the implant reaching the end of itsuseful life, i.e. the drug has been administered for the intended lengthof time or the patient requesting removal of the implant. Theimplantable delivery device can be removed, by pulling on the retrievalmeans 14, for example a cord or hook to withdraw the implant from themyometrium 44. Again, this is a straightforward procedure withoutroutine need for local anaesthetic.

The delivery device is typically removed from the tissue after it hasreleased a therapeutic agent in an amount selected from 5%, 10%, 5%,20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% and 100% relativeto the total amount of medicament in the device after implantation for aperiod of 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 6months, 1 year, 2 years, 3 years, 4 years or 5 years.

Alternative insertion tools may be used to insert the device.

For example if the implant has a blunt first end 4, as illustrated inFIG. 4, an insertion tool with a semi-sharp point may be used topenetrate the myometrium or prostate tissue and enable insertion of theimplant.

This may be advantageous, as the implant which is retained in the tissuedoes not then require to have a semi-sharp portion.

In further embodiments of the insertion tool, instead of or in additionto device mounting means, the insertion tool may comprise means forreleasably containing the implant within the tool. This embodiment ofthe insertion tool is driven into the myometrium, the implantable deviceis released into the myometrium and the tool is then withdrawn leavingthe implant in place. For example, the insertion tool may comprise acollar for releasably retaining the medicament delivery device.

During insertion, use and removal the implantable device may bemanipulated using any suitable surgical tool, such as forceps or thelike.

As discussed above, the implantable medicament delivery device can beprovided with medicament for release into the surrounding tissues in anumber of ways.

Where the medium carrying the active agent of the medicament is providedby the body of the delivery device, the agent is released from themedium and passes through drug delivery means present in the deliverydevice to enter the surrounding tissue, for example the myometrialtissues. Drug delivery means may be provided along the entire length, atleast part of the body, the head, or the body and head of theimplantable device.

When inserted in the myometrium the body of the medicament deliverydevice is surrounded by smooth muscle and soft tissue. As smooth muscleof the cervix is highly vascularised, drug delivery to these tissuesshow good pharmacokinetics.

These drugs are able to pass through the highly vascularised tissues ofthe myometrium and target the pelvic region and organs thereof, forexample, the bladder, peritoneum, and in females the vulva, vagina,ovaries and uterus. The drugs may further enter the bloodstream withoutbeing subjected to first pass liver metabolism.

Alternatively, drug delivery means may be provided at the head portionat the second end of the delivery device. When, in use, the implant isinserted into myometrial tissue, the head portion protrudes from themyometrial tissue into the vagina. In this particular embodiment, theimplant provides a means of targeting drug delivery to the tissues ofthe vagina.

The implantable delivery device may be retained in the myometrium or theprostate and drug delivered over a period of at least, 1 day, 1 to 3months, 1 to 6 months, 1 to 12 months, 1 to 2 years, 1 to 3 years or 1to 5 years.

The implant of the present invention may be used to deliver a wide rangeof drugs. In particular, the implant can be used to deliver drugs whichcannot be delivered orally.

Examples of conditions which can be treated using the drug deliverydevice will now be provided.

Endometriosis

Endometriosis is a painful condition caused by the endometrium (cellslining the uterus) migrating to other parts of the body. This can causefunctional and hormonally responsive endometrial lesions. Typicallylesions are found on the uterine muscles, ovary, peritoneum andintestine. Symptoms of endometriosis include excessive bleeding,dysmenorrhoea, pelvic pain and infertility (up to 60% of women sufferingfrom endometriosis become infertile).

Fibroids

Fibroids or myoma are benign encapsulated tumours of the smooth muscleand/or fibrous tissue elements of the uterine myometrium. They areusually asymptomatic, but may give rise to menstrual and/or fertilityproblems.

At present, an oral treatment (Danazol) is one of the most effectivedrugs to treat endometriosis, but the androgenic side effects of thisdrug limits treatment to 6 months. Endometriosis can also be treatedusing subcutaneous depot injections or nasal sprays of GnRH analogues.However, these treatments also have unpleasant side effects such as bonedensity loss, hot flushes and nausea.

The present implantable medicament delivery device providespharmacokinetic advantages over the above for the treatment ofendometriosis and fibroids. In particular the present delivery systemprovides long term delivery of a drug locally to the pelvic region,without the disadvantage of current local delivery systems such asvaginal rings or intrauterine devices.

A number of active agents may be provided using the device of thepresent invention for treatment of endometriosis.

Progestin

Progestins have advantages over Gonadotrophin Releasing Hormone (GnREH)Agonists in that they are cheaper with an improved side effect profile.In addition. Progestin therapy is most effective in controlling thesymptoms associated with endometriosis, more specifically dysmenorrhea.

Progestin refers to synthetic progestogens wherein Progestogen is ageneric term for all substances with progesterone like activity.Progesterone refers to the natural progesterone molecule.

There are two main groups of progestogen, progesterone and its analogues(dydrogesterone, gestrinone and medroxyprogesterone) and testosteroneanalogues (norethisterone and norgestrel). The newer progestogens(desogestrel, megestrol, norelgestromin, norgestimate, etonogestrol,etynodiol or ethiynodiol and gestodene) are all derivatives ofnorgestrel; levonorgestrel is the active isomer of norgestrel and hastwice its potency. Progesterone and its analogues are less androgenicthan the testosterone derivatives. Testosterone analogues are thenorethindrone family (estranes)—including norethindrone, norethindroneacetate, ethynodiol diacetate, lynestrenol, and norethisterone acetate;and the levonorgestrel family (gonanes)—including levonorgestrel,norgestrel, desogestrel, norgestimate, gestodene, megestrol,norelgestromin, and etonogestrol.

Common progestins include medroxyprogesterone and levonorgestrel.

Non Steroidal Anti Inflammatory Drugs (NSAIDS)

Non Steroidal Anti Inflammatory Drug (NSAIDs) have good efficacy, lowcost and comparatively mild side effect profile, and offer immediatepain management. They are most effective in controlling the symptomsassociated with endometriosis. Common NSAID's include mefenamic acid,diclofenac or piroxicam.

GnRH Analogues

The main therapy shown to improve the severity of endometriosis is thegonadotrophin releasing hormone (GnRH) agonists.

However, this class suffers two main drawbacks, these being cost andsevere side effects profile primarily bone density loss associated withinducing a temporary chemical menopause. Common GnPH agonists includeleuprolide, goserelin and nafarelin.

In addition to the above sole therapies the device of the presentinvention can also be used to deliver a number of combination therapies.For example,

Progestin/NSAID.

Progestin/GnfR analogues,

GnRH/NSAID or,

GnRH add back therapy (tibolone)

GnRH with Add Back Therapy

Add-back therapy in conjunction with a GnRH agonist does not eradicatebone loss, however it does reduce the rate of bone demineralization andhence, enable longer use of GnRH agonists. The progestin tibolone is ofparticular interest for use as add back therapy, particularly forosteoporosis prophylaxis,

Owing to the poor solubility of all proposed drugs in water, a hydrogel(flooded with water, thus low driving force only required to releasedrugs) is ideally used as the drug carrier on the implant. The porousbut permeable active drug/carrier can be coated onto the body of theimplant via mechanical/adhesive hold. In such an embodiment amicroporous implant may be necessary. This exterior coating ofhydrogel/active drug may be biodegradable and should be a highlyconcentrated but thin layer (high drug reservoir/low distance to travel)to obtain maximum rate of drug release via an erosion mechanism.

The amount of drug required to elicit effect can be determined by thoseskilled in the art, using conventional means. However, estimates of theamount of a drug which may be provided based on preliminary resultswhich should not be considered limiting in any way on the device of thepresent invention are given below by way of example only.

Levonorgestrel

Currently, oral daily doses for levonorgestrel are 60 mcg. Using vaginaldelivery analogy of 10% drug required compared to oral doses, dailymyometrial doses would be 6 mcg for levonorgestrel

A more feasible daily dose to enable drug delivery via a hydrogel wouldlikely be 20 mcg for levonorgestrel (33% of oral dose)

Assuming 50% w/w of drug to hydrogel, the total weight of thedrug/carrier layer could be in the range of 3 to 15 mg.

The body of the implant could accommodate 3, 6 or 12 month or longerdoses.

Leuprolide

Currently, the daily dose for leuprolide is 125 mcg (intramuscular).Typical daily myometrial doses could be around 62 mcg for leuprolide(50% of intramuscular dose)

However in the absence of clinical data, it is impossible to estimatethe clinical effectiveness of such doses of leuprolide.

Assuming 50% w/w of drug to hydrogel, the total weight of thedrug/carrier layer would be in the range of 10 m to 45 mg.

The body of the implant could accommodate 3, 6 or 12 month or longerdoses.

Piroxicam

Currently, oral daily doses for piroxicam are 10 to mg. Using vaginaldelivery analogy of 10% drug required compared to oral doses, a dailymyometrial doses could be 3 mg for piroxicam. A more feasible daily doseto enable drug delivery via a hydrogel could be 300 mcg for piroxicam(1% of oral dose), However in the absence of clinical data, it isimpossible to estimate the clinical effectiveness of such low doses ofpiroxicam.

Assuming 50% w/w of drug to hydrogel, the total weight of thedrug/carrier layer would be around 50 to 220 mg.

The body of the implant could accommodate 3, 6, or month or longerdoses.

Levonorgestrel/Piroxicam

Currently, oral daily doses for levonorgestrel are 60 mcg, and piroxicam10-40 mg. Using vaginal delivery analogy of 10% drug required comparedto oral doses, daily myometrial doses could be 3 mg for piroxicam 6 mcgfor levonorgestrel. A more feasible daily dose to enable drug deliveryvia a hydrogel (levonorgestrel dose as per Mirena coil dose) would be300 mcg for piroxicam (1% of oral dose), 20 mcg for levonorgestrel (33%of oral dose). However in the absence of clinical data, it is impossibleto estimate the clinical effectiveness of such low doses of piroxicam.

Assuming 50% w/w of drug to hydrogel, the total weight of thedrug/carrier layer would be in the range of around 55 mg to 230 mg.

The body of the implant could accommodate 3, 6, 12 month or longerdoses.

Levonorgestrel/Leuprolide

Currently, daily doses for levonorgestrel are 60 mcg (oral), andleuprolide 125 mcg (intramuscular). Using vaginal delivery analogy of10% drug required compared to oral doses, daily myometrial doses couldbe 62.5 mcg for leuprolide and 6 mcg for levonorgestrel. A more feasibledaily dose to enable drug delivery via a hydrogel would be 62.5 mcg forleuprolide (50% of intramuscular dose) and 20 mcg for levonorgestrel(33% of oral dose). However in the absence of clinical data, it isimpossible to estimate the clinical effectiveness of such low doses ofleuprolide.

Assuming 50% w/w of drug to hydrogel, the total weight of thedrug/carrier layer could be in the range of around 14 mg to 60 mg.

The body of the implant could accommodate 3, 6, 12 month or longerdoses.

Leuprolide/Tibolone

Currently, daily doses for leuprolide are 125 mcg (intramuscular), andtibolone 2.5 mg (oral). Using vaginal delivery analogy of 10% drugrequired compared to oral doses daily myometrial doses could be 62.5 mcgfor leuprolide (50% of intramuscular dose) and 250 mcg for tibolone.However in the absence of clinical data, it is impossible to estimatethe clinical effectiveness of such doses of leuprolide.

Assuming 503 w/w of drug to hydrogel, the total weight of thedrug/carrier layer would be in the range of around 55 mg to 225 mg.

The body of the implant could accommodate 3, 6 or 12 month or longerdoses.

Leuprolide/Piroxicam

Currently, daily doses for leuprolide are 125 mcg (intramuscular), andpiroxicam 10-40 mg (oral). Using vaginal delivery analogy of 10% drugrequired compared to oral doses daily myometrial doses could be 62.5 mcgfor leuprolide and 3 mg for piroxicam,

A more feasible daily dose to enable drug delivery via a hydrogel couldbe 62.5 mcg for leuprolide (50% of intramuscular dose) and 300 mcg forpiroxicam (1% of oral dose). However in the absence of clinical data, itis impossible to estimate the clinical effectiveness of such doses ofpiroxicam and leuprolide.

Assuming 50% w/w of drug to hydrogel, the total weight of thedrug/carrier layer would be in the range of around 65 mg to 261 mgrespectively.

The body of the implant could accommodate 3, 6 or 12 month or longerdoses.

Bacterial Vaginosis

Bacterial vaginosis, an abnormal colonisation of the vagina which maylead to vaginitis, is an inflammation which occurs in the vagina. Itincludes several strains of organism that cause bacterial vaginosis,yeast infections and trichommoniasis. Bacterial vaginosis occurs mostlyduring the reproductive years although women of all ages aresusceptible. Typically infection affects the vagina, urethra, bladderand skin in the genital area.

Primary-causes of bacterial vaginosis include an overgrowth of anaerobicbacteria and the Gardnerella organism. Although the healthy vaginaincludes a small amount of these bacteria and organisms, when thevaginal balance is disrupted by the overgrowth of these bacteria,another protective aerobic bacterium (lactobacilli) is unable toadequately perform its normal function. Lactobacilli normally provides anatural disinfectant (similar to hydrogen peroxide) which helps maintainthe healthy and normal balance of microorganisms in the vagina. Thevaginal anaerobic to aerobic bacteria ratio is 1000 to 1, normal vaginalflora is 5 to 1 ratio. During vaginosis a change in pH of vaginal fluidalso occurs.

Bacterial Vaginosis can cause a range of symptoms such as discharge. Inaddition, the change in pH of the vaginal fluid to more than 4.5 canalso cause odour and some itching.

The medicament delivery device of the present invention may be used todeliver medicaments to restore normal vaginal bacteria by inhibitinganaerobic bacteria, but not the normal vaginal lactobacilli, in order toeliminate symptoms of discharge and odour.

In particular embodiments, one of which is illustrated in FIG. 2 anddiscussed above, the medicament delivery device has a body portion forinsertion into the myometrium and a head portion which extends into thevaginal cavity. The body portion is preferably around 5 mm to 20 mm inlength and the head portion is around 10 to 12 mm in width.

In this embodiment the medicament is contained or absorbed by or coatedonto the head portion of the device such that it can be released overtime into the vaginal cavity. Any suitable pharmaceutical means may beused to carry the drug and enable its release over time to the vaginalcavity.

Drugs which may be used to treat bacterial vaginosis include Flagyl(also known as Metronidazole), acidifiers to decrease pH to less than 5,less than 4.5, prebiotics, and probiotics. Other treatments includecleocin, ampicillin, ceftriaxone and tetracycline. Other drugs suitablefor treating bacterial vaginosis such as pH regulators, suitableantibiotics and other drugs will be known to those skilled in the art.

The location of the implant in the smooth muscle myometrium of thecervix and/or part of the body of the smooth muscle myometrium of theuterus allows the implant to be easily inserted. During retention of theimplant in the myometrium of the cervix, straightforward examination ofthe vaginal cavity 34 by a medical practitioner can verify that theimplant is in its intended position in the myometrium. Whilst there islittle chance of the implant becoming displaced, as the retrieval means,for example the cord or hook and in particular embodiments the headportion remains outside the myometrium, any such displacement can beeasily observed.

Various improvements and modifications may be made without departingfrom the scope of the present invention. For example, as detailed abovethe body of the implant may be formed from absorbable polymers. Thiswould avoid the need to remove the implant at a later date. Any suitableretrieval means can be provided on the implant to allow the implant tobe moved into and out of the tissue of the myometrium or prostate.

1-24. (canceled)
 25. An implantable medicament delivery deviceinsertable into the female uterine myometrium to provide controlleddelivery of a medicament over a period of time said device comprisingmeans for providing controlled delivery of a medicament, an elongatebody having an outer surface, a first end, and a second end wherein thesecond end includes a head portion wherein the head portion is a lateralextension from the longitudinal axis of the elongate body and the headportion allows manipulation and surveillance of the implant.
 26. Theimplantable device of claim 25, wherein the means to provide controlleddelivery of the medicament is provided in or on the body of the implant.27. The implantable device of claim 26, wherein, in use, when insertedin the myometrium, the body of the medicament delivery device issurrounded by smooth muscle and soft tissue of the myometrium and themedicament passes through the smooth muscle and soft tissue and targetsthe pelvic region and organs thereof.
 28. The implantable device ofclaim 25, wherein the means to provide controlled delivery of amedicament is provided in or on the head portion of the implant.
 29. Theimplantable device of claim 28, wherein, in use, when the device isinserted into myometrial tissue, the head portion protrudes from themyometrial tissue into the vagina and targets the medicament to thetissues of the vagina.
 30. The implantable device of claim 25, whereinthe first end of the body has a semi-sharp point.
 31. The implantabledevice of claim 25, wherein the device is absorbable.
 32. Theimplantable device of claim 25, wherein the head portion is asubstantially flat plate which extends in all radial directions from thesecond end of the body of the device.
 33. The implantable device ofclaim 25, wherein the second end comprises retrieval means.
 34. Theimplantable device of claim 33, wherein the retrieval means is anelongate flexible member.
 35. The implantable device of claim 25, whichhas an axial length from 5 mm to 45 mm.
 36. The implantable device ofclaim 25 which has a diameter of from 0.5 mm to 4 mm.
 37. Theimplantable device of claim 25, comprising at least one medicament. 38.The implantable device of claim 37, wherein the least one medicament isselected from anti-infectives, antimicrobials, prebiotics, probiotics,acidifiers, antivirals, antibiotics, anti-allergenics,anti-inflammatories, anti-fungals, anti-cholinesterases, nutritionalagents, cardiovascular agents, anti-hypertensive agents, andchemotherapeutic agents.
 39. The implantable device of claim 37, whereinthe device comprises a medicament for oestrogen dependent proliferativedisorders of the pelvis for example endometriosis or fibroids.
 40. Theimplantable device of claim 37, wherein said the medicament is at leastone member chosen from the group including progestins, GnRHagonists/antagonists, NSAIDs, COX-II inhibitors, combined oralcontraceptives, Danazol, smooth muscle relaxants or aromataseinhibitors.
 41. The implantable device of claim 25, wherein, in use, thecumulative release of medicament is in an amount selected from 5%, 10%,15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% relative tothe total amount of medicament in the device after implantation for aperiod of 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months,6 months, 1 year, years, 3 years, 4 years or 5 years.
 42. Theimplantable medicament delivery device of claim 25, wherein said deviceis provided in a kit for introducing said medicament delivery deviceinto a mammal, the kit also comprising an insertion tool comprising anelongate shaft, said shaft having a handle means at a first end thereofand device mounting means at a second opposite end wherein themedicament delivery device is mountable on the device mounting means ofthe insertion tool.
 43. A method for introducing a medicament into thebody of a female mammal, comprising the steps of: providing animplantable medicament delivery device, said device capable of providingcontrolled delivery of a medicament over a period of time into amyometrium; and introducing the medicament delivery device into themyometrium of a uterine body through serosa surrounding the myometriumduring open or laparoscopic surgery.
 44. A method for introducing amedicament into the body of a female mammal, comprising the steps of:providing an implantable medicament delivery device; introducing themedicament delivery device into the body via the vagina; penetrating themyometrium via the uterine cervix; and inserting the medicament deliverydevice into the myometrium.